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Induced pluripotent stem cell intervention rescues ventricular wall motion disparity, achieving biological cardiac resynchronization post-infarction

Authors

  • Satsuki Yamada,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
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  • Timothy J. Nelson,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
    3. Division of General Internal Medicine, William J. Von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA
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  • Garvan C. Kane,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
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  • Almudena Martinez-Fernandez,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
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  • Ruben J. Crespo-Diaz,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
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  • Yasuhiro Ikeda,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
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  • Carmen Perez-Terzic,

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
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  • Andre Terzic

    1. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
    2. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA
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A. Terzic: Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: terzic.andre@mayo.edu

Key points

  • • The pumping function of the heart depends on ordered initiation and propagation of myocardial excitation. Cardiac output is compromised by inconsistent timing and direction of wall motion, leading to dyssynchrony and organ failure.
  • • Myocardial infarction induces irreversible heart damage. Extensive damage hampers effective pacemaker-based cardiac resynchronization therapy, the current standard-of-care. Establishment of alternative approaches is thus warranted.
  • • High-resolution imaging was here utilized to non-invasively map suitable therapeutic targets within a dyssynchronous heart. Speckle-tracking echocardiography unmasked the source of progressive cardiac dyssynchrony within the primary infarcted region.
  • • Bioengineered stem cells with a capacity to induce a regenerative response were implanted into infarcted areas. Speckle-tracking echocardiography and histology assessment revealed that cell therapy achieved cardiac resynchronization and long-term repair.
  • • This proof-of-concept study thus introduces a stem cell-based regenerative solution to address cardiac dyssynchrony post-infarction.

Abstract  Dyssynchronous myocardial motion aggravates cardiac pump function. Cardiac resynchronization using pacing devices is a standard-of-care in the management of heart failure. Post-infarction, however, scar tissue formation impedes the efficacy of device-based therapy. The present study tests a regenerative approach aimed at targeting the origin of abnormal motion to prevent dyssynchronous organ failure. Induced pluripotent stem (iPS) cells harbour a reparative potential, and were here bioengineered from somatic fibroblasts reprogrammed with the stemness factors OCT3/4, SOX2, KLF4, and c-MYC. In a murine infarction model, within 30 min of coronary ligation, iPS cells were delivered to mapped infarcted areas. Focal deformation and dysfunction underlying progressive heart failure was resolved prospectively using speckle-tracking imaging. Tracked at high temporal and spatial resolution, regional iPS cell transplantation restored, within 10 days post-infarction, the contractility of targeted infarcted foci and nullified conduction delay in adjacent non-infarcted regions. Local iPS cell therapy, but not delivery of parental fibroblasts or vehicle, prevented or normalized abnormal strain patterns correcting the decrease in peak strain, disparity of time-to-peak strain, and pathological systolic stretch. Focal benefit of iPS cell intervention translated into improved left ventricular conduction and contractility, reduced scar, and reversal of structural remodelling, protecting from organ decompensation. Thus, in ischaemic cardiomyopathy, targeted iPS cell transplantation synchronized failing ventricles, offering a regenerative strategy to achieve biological resynchronization.

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